# Bioinorganic Explorations of Host-Defense Proteins

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2020 · $272,092

## Abstract

PROJECT SUMMARY
Transition metal ions are essential nutrients for all organisms. The availability of these nutrients plays a critical
role in the host-microbe interaction and microbial pathogenesis. The primary objective of this research
proposal is to elucidate how the host-defense protein calprotectin (CP) sequesters transition metals from
microbes and thereby contributes to the innate immune response. CP provides a remarkable example of
unique biological coordination chemistry that is relevant to infectious disease and microbial pathogenesis.
Each CP heterodimer (S100A8/S100A9) exhibits six different sites for chelating divalent cations, including
calcium (Ca) and transition metals. Our central hypothesis is that CP responds to physiological Ca(II)
gradients to tune its coordination chemistry for transition metals and to modulate its biological function as an
antimicrobial protein that deprives invading pathogens of essential nutrient metals (e.g. manganese, iron, zinc).
The proposed investigations are based on preliminary data that Ca(II) binding by human CP (hCP) at the EF-
hand domains triggers high-affinity chelation of transition metals at sites formed at the interface of the S100A8
and S100A9 subunits. In Aim 1, we will investigate how Ca(II) ions modulate hCP structure and tune its
affinities for transition metals. In Aim 2, we will evaluate how the murine orthologue (mCP) sequesters
transition metals and thereby provide needed molecular and biophysical insights into literature results of CP
from animal models of infection. In Aim 3, we will investigate the competition between CP and bacterial metal-
transport machinery for manganese(II). These fundamental bioinorganic and biophysical initiatives constitute
an innovative departure from biological and medical studies of CP, and highlight the importance of applying
quantitative analytical and spectroscopic methods to a problem central to human health and disease. Taken
together, the results will provide new molecular insights into how CP contributes to innate immunity and metal
homeostasis. Moreover, the ability to acquire metal ions is an important facet of microbial pathogenesis, and
both intercepting microbial metal acquisition and boosting the metal-withholding response of the host present
opportunities for antibiotic development. We anticipate that the results from our work will, in the long term, help
to guide the development of new antimicrobial therapeutics that target these processes central to the host-
pathogen interaction.

## Key facts

- **NIH application ID:** 9982335
- **Project number:** 5R01GM118695-04
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** ELIZABETH M NOLAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $272,092
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982335

## Citation

> US National Institutes of Health, RePORTER application 9982335, Bioinorganic Explorations of Host-Defense Proteins (5R01GM118695-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9982335. Licensed CC0.

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